It is generally accepted that hormonal replacement therapy in postmenopausal women, besides many beneficial therapeutical effects, increases the risk of breast or endometrial cancer, at least after a prolonged treatment (1).
If all responses to estrogen were mediated by the same mechanism and all ERs were identical, as it was first reported for the cytosol-nuclear receptor-mediated genomic responses (2), the possibility to selectively induce therapeutically convenient responses to estrogen, but not those at risk (cell proliferation), would be scarce.
The finding in our Laboratory of the first non-genomic mechanism of estrogen action in the uterus and its investigation in depth for more than 30 years (3-11), revealed the existence of multiple kinds of estrogen receptors, involved in various independent groups of responses to estrogen stimulation through separate mechanisms of hormone action (4, 8, 9, 11-14). Among them, cytoplasmic membrane hormone receptors (15, 16), type II estrogen cytoplasmic and nuclear receptors (17) and specific antiestrogen receptors (18); more recently, immunochemical (19) and ligand (20) differences between two kind of the classical “cytosol-nuclear receptors” were reported; these receptors were named α and β ERs (21). The differences between receptors and the mechanisms of estrogen action involved, and the independence between the various groups of responses to hormone stimulation, allow the dissociation of responses to estrogens into separate groups, which can be selectively stimulated, inhibited or completely blocked.
Several agents or conditions were already reported to dissociate the various estrogenic responses in same animal. Among them, the route of estrogen administration allowing physiological hormone levels locally or systemically (22), the use of different estrogenic compounds, such as estriol (23), estradiol-17α (11), diethylstilbestrol (14), clomiphene (24), nafoxidine (12, 25), 2(OH)-estradiol-17β or 4(OH)estradiol-17β (26); the interaction with other hormones such as glucocorticoids (27), progesterone (28), insulin (29) or thyroid hormones (30); the administration of various pharmaceuticals or biological reagents such as theophylline (31), bromocriptine (32); actinomycin D (33) or colloidal carbon (13), and the exposure to environmental pollutants such as lead (34) or DDT (35). This dissociation opens a new therapeutic approach, to selectively induce desired responses of estrogen stimulation, without the simultaneous induction of responses considered at risk (endometrial or mammary cell proliferation).
There are several reports indicating lower incidence of breast cancer in Asian women than in Western women (36); this difference in breast cancer incidence parallels the significantly higher amount of phytoestrogens—including soybean products—consumed by Asian women (36). Second- and third-generation descendants of women who migrated from Asia to Western countries have breast cancer risks similar to those of women in the host country, suggesting that lifestyle and not genetic factors explain the low breast cancer risk observed in Asian women (37, 38). In East and Southeast Asia the average intake of phytoestrogens is estimated to be more than ten times higher than in the United States or Europe (39), and plasma isoflavone concentrations are much higher in Japanese women than in Europeans, suggesting their role in breast cancer prevention (40).
Taking into consideration epidemiologic evidence suggesting that Oriental countries preferential diet containing soy products—rich in glucosides of estrogenic isoflavones such as genistein (41), may protect against breast cancer development (40, 42-44), our research interest was turned to investigate whether these compounds are able to selectively induce some but not all responses to hormone stimulation in the uterus, for their potential use as therapeutic agents for hormonal replacement therapy devoid of neoplastic risk. For this purpose, we initially investigated the in vivo estrogenic agonistic effects of chemically pure genistein and of phytoestrogens present in soybean extracts on various parameters of estrogen action in the rat uterus, and the in vitro cell proliferation of two mammary cancer cell lines in tissue culture.
For further background to this disclosure is the fact that ancestral populations used, for centuries, several native plant species for specific health needs such as menstrual pain, menstrual cycle normalization, dysmenorrheal and other disorders. According to ethno/medicinal knowledge there are numerous plant species useful for treatment of several “diseases” which actually are clinical symptoms. Several compounds have been identified in many of these plant species, but there is no knowledge about which of these compounds are involved in the therapeutic effects indigenous population claim to exist. Further, there is no scientific demonstration of the effectiveness of the therapeutic effects nor is there knowledge on the molecular mechanisms involved.
Subsequently, we incorporated into the study extracts and decoctions of various plant species, chosen according to ethno-medicinal knowledge that they displayed any gynecologic or sex hormone activity or interfered with reproductive physiology.